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138 Cards in this Set
- Front
- Back
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Which components of LADME are associated with PO only?
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Liberation and Absorption
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Non-linear kinetics involves _______________ systems.
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Saturable
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What is the unit for F?
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There is none
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Moxifloxacin IV bioavailable fraction?
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1
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Formula for F for oral formulation?
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F = ffp x fa
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ffp means?
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Fraction escaping 1st pass
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fa means?
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Fraction absorbed
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Relationship of CL to T1/2
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Inverse
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Unit of CL
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L/hr
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Normal Hepatic Blood Flow
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90 L/hr
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A drug with a CL of 88 and HBF of 90 would be called what?
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A high E (efficiency drug)
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Why is IBW used when calculating CL?
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Because obesity does not affect the size of the clearing organ
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IBW formula for men
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50kg + 2.3kg per inch over 60
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IBW formula for women
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45.5kg + 2.3 kg per inch over 60
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Does Vd affect CL?
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Yes
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Does T1/2 affect Vd?
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No
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After how many T1/2s are most drugs considered to be effectively gone?
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5
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What does a zero input mean when administering a drug?
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The drug is administered as a continuous infusion
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What is Emax?
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The maximumal pharmacodynamic response
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T / F Emax only occurs when all receptors are occupied?
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False
Emax CAN occur if all receptors are occupied, but doesn't have to |
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Describe the Fixed Effect PD model
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1 or 0 - present or not
Threshold can very |
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What is the EC50 in terms of the sigmoid Emax model?
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The effective concentration producing half maximal effect
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In terms of the Sigmoid Emax model, what does E0 mean?
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It is the background effect factor that shifts the curve upwards
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Describe the logarithmic PD model
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Linearizes the sigmoid max model when looking at the 20-80% Emax, limited. Allows for comparison of potency/competetive model
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Describe the Linear model
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E = S x C
S = Slope parameter Fucking useless, move on |
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Describe the Sensitization model for PD
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Higher on the way down since the receptor is now horny.
Its in a counterclockwise graph |
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Describe the tolerance model
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Lower on the way down, receptors begin to ignore (afrin)
Clockwise graph |
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In a single compartmental model, is increasing the dose an efficent way to increase effect?
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No - The Y-axis is in logarithmic form and time is in linear, so giving a 2nd dose at a later time such as when there is loss of effect will give a greater/longer effect
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Describe what influences duration of effect in a multicompartmental model
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Depends on distribution and depth (amt of drug present and rate of input/output).
Is not a function of dose. |
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Describe the effect of giving the same total dose over shorter intervals on AUC and Css
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AUC will increase.
Css will remain the same |
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________ drug is available for effect and clearance typically.
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Unbound
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Why can total drug concentration be used for dose adjustment (although total drug will not necessarily be causing the effect)
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It is typically proportional to the unbound fraction, which is available for effect and clearance.
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Where is albumin made?
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Liver
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What is the Alb half life?
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19 days
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Where is Albumin predominately found? Extra/intra vascular?
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Extravascular
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What types of drugs does albumin bind?
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Acidic and neutral mostly
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What are the two binding sites of albumin?
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Warfarin and indole-bzd
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What can cause alb to have a confirmational change and displace other drugs?
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Bilirubin
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Sulfonamides, binding site
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Warfarin ALB
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Alb binding site: Sulfonamides
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Warfarin
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Alb binding site: Phenytoin
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Warfarin
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Alb binding site: VPA
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Warfarin - very pushy
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Alb binding site: NSAIDs
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Both
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Alb binding site: Semisynthetic PCNs
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Indole bzd
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Alb binding site: Probenicid
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Indole-bzd
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Alb binding site: Medium chain FA
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Indole - bzd
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AAG binds what types of drugs
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Basic/neutral
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Which binding protein is considered "Acute phase reactive"
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AAG
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What can affect AAG production?
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Stress mediated by cytokines
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T1/2 of AAG
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5 days (short)
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AAG is predominantely:
A: Extravascular B: Intravascular |
B
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Liver Dz, effect on Albumin
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Decrease
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Lipoproteins bind what types of drugs?
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Basic / neutral
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Describe saturation of Lipoproteins
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Many drugs Cannot be saturated since partitioned into core
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Which drugs are partitioned into the core of lipoproteins?
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Cyclo, probucol, dig, sirolimus, pindolol
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Cyclosporin Binding (binding lecture)
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Lipoprotein core
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Dig binding (binding lecture)
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Lipoprotein core
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Sirolimus Binding
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Lipopreotein core
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TCA binding
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Protein component of lipoprotein, saturable
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Quinidine binding
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Protein component of lipoprotein, saturable
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Which drugs bind to the protein component of lipoprotein (saturable component)
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TCAs / Quinidine
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Describe altered drug binding in: Neonates
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-Alb
-AAG +Bili/FFAs |
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Describe altered drug binding in: Elderly
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- Alb
Glycosylation of Alb/AAG (altered affinity) |
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Describe altered drug binding in: Pregnancy
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-Alb
+FFA -AAG |
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Which drugs will have a higher fu in pregnancy?
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Salicylates
Phenytoin Valium VPA |
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Describe normalization of proteins after delivery of a baby (small human)
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AAG/FFA in a few days, Alb in a month
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Describe altered drug binding in: Obesity
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No effect
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Describe altered drug binding in: Smoking
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No effect
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Describe altered drug binding in: Diurnal
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AAG/FFAs (Lipoproteins) due to food/cytokines
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Describe altered drug binding in: Nephrotic syndrome
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-Alb
+AAG |
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Describe altered drug binding in: Uremia
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Drug displacement/confirmational changes
+AAG |
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Describe what drugs would have major changes in protein binding in uremia or nephrotic syndrome
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Phenytoin
MPA Fibrates WILL ALL +fu |
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Describe altered drug binding in: Trauma
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+AAG
-Alb |
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Describe altered drug binding in: OCP use
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-AAG
Increase lido/valium levels |
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Phenytoin population value for Vm
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Vm = 7
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Phenytoin population value for Km
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5
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Initial dose equation for phenytoin
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Below equals dose
(Vm x Cp) ------------ Km + Cp |
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How do you calculate Vm for phenytoin once a lab value is known?
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Below equals Vm
Km x Dose ---------- + Dose Css |
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Phenytoin
What is Km |
[] at which rate of metabolism is 1/2 the max rate, Vm
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Phenytoin, what is Vm
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The maximum rate of metabolism
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Phenytoin
If C <<< Km, what happens? |
1st order
Vm x Cp Vm x Cp --------- => -------- Km + Cp Km (Km + Cp) ==> Km |
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At low doses, Phenytoin follows _____ order kinetics
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1st order
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At high doses,phenytoin follows _____ order kinetics
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Zero
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Ideal therapeutic range for Phenytoin
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10-20
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Phenytoin metabolism in peds
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Faster
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Phenytoin metabolism in old people
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Slower, no one cares though
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How long does phenytoin take to reach Css?
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2 weeks, unless Km is lower
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Phenytoin is a substrate of what enzyme?
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CYP 2C9
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What happens if Albumin tanks to phenytoin?
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+fu --> + effects (lower dose) AND + CL (lower total level)
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What would be the effect on Vmax of co-administration of phenytoin with CBZ or phenobarbital?
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Increased due to induction
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What would be the effect on Vmax of Cirrhosis for phenytoin?
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Decreased
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What would be the effect of competitive inhibition on Km for Phenytoin?
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Increased, need more drug to overcome inhibition
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What would be the effect of decreased albumin on Km for phenytoin?
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Lower (More available to be chewed up)
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Effect of renal dysfunction on Phenytoin
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+/- preotein and lft effects
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What would be the effect of microalbuminuria on phenytoin levels?
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- Alb
- Total level + Fu |
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Dose related ADRs of Phenytoin
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Drowsiness
Confusion Nystagmus Ataxia Slurred speech Nausea Unusual behavior MS changes Coma |
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Non dose related ADRs of Phenytoin
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Hirsutism, acne, gingival hyperplasia, folate deficiency, osteomalacia, SJS
For these, must change drug |
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CBZ Therapeutic range
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4-12
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Autoinduction of CBZ occurs during which period?
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21-28 days
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At steady state, what is the T1/2 of CBZ?
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12 h
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Describe CBZ levels upon initiation and as times progress
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Levels will be higher earlier on
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CBZ + Food = ?
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Increased absorption with IR --> Toxicity risk
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With what doses is CBZ linear?
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600-1400
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At what doses of IR is CBZ not absorbed well?
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>20mg/kg
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Dosing frequency of CBZ ER
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BID
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CBZ Protein binding
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Highly variable
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Metabolism of CBZ
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99% hepatic, no renal
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What happens if CBZ is administered with other antiepileptics?
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-T1/2 due to 3A4, thus avoid
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VPA absorption
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Well absorbed
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VPA: Effect of EC on PK paramaeters
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Delayed absorption, but no change in extent
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Describe VPA bioequivalence between formulations
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ER not bioequivalent, must increase dose 10-20%
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For what Antiepileptic agent does CSF predict serum concentration?
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VPA
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Gabapentin Elimination
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Renal excretion
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Which Anti-epileptic is the only one that is renally cleared?
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Gabapentin
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Describe entry into CNS of Gabapentin
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Active transport
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Descibe absorption and entry into CNS mechanism for Gabapentin
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active transporter, thus limited
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Describe utility of blood levels for gabapentin
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Nuttin
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Which Anti-epileptic drug is affected by L-amino acid transporters?
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Gabapentin
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CKD
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Chronic Kidney Disease
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3 things CKD can affect
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Distribution
Protein Binding Bioavailability |
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CLr is a composite of what 3 components
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Glomerular filtration(passive)
Tubular Secretion(Active) Tubular reabsorption(Active) |
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What agent is ideal for determining Renal Fx
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Inulin
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What relationship exists between SCr and GFR?
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Inverse
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Utilization of Creatinine to determine kidney function depends on what assumptions?
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1. Constant Cr production
2. Cr is from muscle and constant 3. Cr is filtered only 4. Accurate measurement 5. Urine collection is complete |
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What agent competes for creatinine secretion?
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Cimetidine
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What agent competes for anionic pump (PCN) secretion?
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Probenecid
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Active secretion method
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Carrier mediated (pumps) - Competitive
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What can be filtered by glomerular filtration?
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Free drug
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Mechanisms of renal reabsorption
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1. Active transport
2. Passive back diffusion 3. Endocytosis |
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How can CKD affect Vd?
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Fluid overload
Altered protein binding |
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Protein binding effects caused by end stage renal failure
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-Alb
+AAG |
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Which type of renal failure has more effect on the liver?
(In terms of protein expression) |
Chronic Renal failure
(Protein expression) |
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3 types of Dialysis
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1. Hemodialysis
2. Peritoneal Dialysis 3. Continuous renal replacement therapies |
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Drugs that are highly protein bound are ________ likely to be dialyzed
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Less
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A drug with a large Vd is _____ likely to be cleared by dialysis.
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Less
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How long do you wait before drawing blood levels after dialysis?
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2 hours, allow for redistribution
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Why would you still give a loading dose in a hemodialysis patient for a drug that is poorly removed by dialysis?
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The drug must still fill the Vd, its maintenance doses that must be adjusted
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What is the dosage adjustment factor formula?
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Q = 1 - [Fe (1-KF)]
fe = Fraction eliminatd unchanged KF = CrCL / 120 |
